Process for conditioning substances

ABSTRACT

The present invention relates to a process for providing a stable crystallinic form to a fine-grained substance or a substance mixture, which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation of such a substance or a substance mixture, by 
     a) in case of a substance mixture, preparing a homogenous mixture of the substances; 
     b) micronizing, direct precipitating or diminishing by any conventional method the substance or substance mixture into a particle size required for inhalation, the particle size being less than 10 μm; 
     c) optionally preparing a homogenous mixture of the desired substances when each substance has been introduced from stage b) as separate fine-grained particles; 
     d) conditioning said substance or substance mixture by treatment with a water containing vapor phase in a controlled fashion; and 
     e) drying.

This is a 371 application of PCT/SE94/00780 filed Aug. 25, 1994.

This is a 371 application of PCT/SE94/00780 filed Aug. 25, 1994.

FIELD OF THE INVENTION

The present invention relates to a process for providing a fine-grainedsubstance or substance mixture, which can be produced, stored and usedwhile maintaining the aerodynamic properties required for inhalation ofsuch a substance or substance mixture and which has improvedphysicochemical properties in the dry state, thereby facilitating thetechnical handling and significantly increase the medical value of thesubstance or substance mixture used.

BACKGROUND OF THE INVENTION

There are presently several effective drugs available for the treatmentof patients with asthma or other respiratory disorders. It has beenrecognized that these drugs should be given by the inhaled routewhenever possible. The ideal delivery system for inhalable drugs wouldbe a user- and environment-friendly multidose inhaler giving accuratedoses of a stable formulation with good aerodynamic behaviour of theparticles.

During the past few years, there have been frequent demonstrations ofthe fact that the appropriate selection of the most suitable crystallinemodification significantly can influence the clinical results of a givenchemical substance. The chemical and physical stability of a solid in aparticular dosage form can be improved by presenting the substance(s) inthe appropriate crystal form. The solid state phase transformation ofthe substance in a dosage form can dramatically alter the pharmaceuticalproperties of the formulation. The solid state phase of the administeredsubstance(s) can influence such important factors as bioavailability andphysicochemical stability (specific surface area, particle size etc).Chemical stability in solid state and hygroscopicity are often closelyrelated to the crystallinity.

Solid state transformations may occur during mechanical processing e.g.micronization. In a micronization process of solids, disruption oractivation of the crystalline structure often leads to varying degreesof disorder through the formation of defects or amorphous regions. Suchregions are often more sensitive to external effects e.g. moisture. Itis necessary to establish the conditions whereby different forms of asubstance might be converted to a single stable form thus eliminatingdifferences in solid state properties and subsequent differentphysicochemical and pharmaceutical properties.

The increasing production and use of fine powders in the pharmaceuticalindustry has highlighted the need of reliable methods for assessingtheir physicochemical and technical handling. Mixing of cohesive powderswill be influenced by the interparticulate forces between particles ofthe same species and also between particles of different species. Sincefine powders agglomerate, the mixture will often be inhomogeneous,particularly the minor component will show a skewed distribution. Onereason could be that the agglomerates of the minor component are notcompletely dispersed into their component particles; see further Chem.Eng. (1973), 12-19. Cohesive powders are thus very difficult to mix to ahomogenous mixture in an accurate way, especially when one component ispresent only as a small fraction.

Substances will often be obtained in an amorphous state or a metastablecrystalline form when spray drying, freeze drying, rapid solventquenching or when using controlled precipitation, where both crystallineand amorphous forms can be prepared. The use of an amorphous form ormetastable crystalline form is often limited due to its thermodynamicinstability. It is therefore a desire to convert the amorphous form orthe metastable crystalline form to the more stable crystalline state.For crystalline substances, a diminution operation step will giveamorphous regions of the particle making the particle more sensitive tomoisture and chemical degradation. The present invention deals with suchphysical changes, or more importantly, to anticipate them and the meansby which these solid state phenomena can be handled.

The rearrangement or conditioning of a water-soluble substance,amorphous or partly amorphous, using a solvent like ethanol, acetone orthe like has been described in Eur. Pat. Appl. EP 508 969 where singlecompounds have been treated. However, that method is not applicable forsome substances containing crystal water, since organic solvents willeliminate the water thereby changing the properties of the substanceconsiderably. It has been understood that water-soluble substances couldnot be conditioned by water while keeping the particle distribution of afine-grained substance intact.

References:

Amorphous-to-Crystalline Transformation of Sucrose, Phar. Res., 7(12),1278 (1990) by J. T. Carstensen and K. Van Scoik.

Effect of Surface Characteristics of Theophylline Anhydrate Powder onHygroscopic Stability, J. Pharm. Pharmacol. 42, 606 (1990) by M. Otsukaet al. Process for conditioning of water-soluble substances, Eur. Pat.Appl. 508969 by J. Trofast et al. The molecular basis of moisture effecton the physical and chemical stability of drugs in the solid state, Int.J. Pharm. 62(1990), 87-95 by C. Ahlneck and G. Zografi.

DESCRIPTION OF THE DRAWING

FIG. 1 shows the amount of heat evolved over time duringrecrystalization of micronized lactose before (I) and after (II)conditioning.

BRIEF DESCRIPTION OF THE INVENTION

The object of the invention is to provide a process for a fine-grainedsubstance or substance mixture, which can be produced, stored and usedwhile maintaining the aerodynamic properties required for inhalation ofsuch a substance or substance mixture, by conditioning the substance orsubstance mixture in a controlled process, thereby facilitating thetechnical handling and significantly increasing the medical value of thesubstance or substance mixture.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide a reliable process forproviding a stable crystallinic form to a fine-grained substance or asubstance mixture, which can be produced, stored and used whilemaintaining the aerodynamic properties required for inhalation of such asubstance or a substance mixture. The process according to the presentinvention comprises the following steps:

a) in case of a substance mixture, preparing a homogenous mixture of thesubstances;

b) micronizing, direct precipitating or diminishing by any conventionalmethod the substance or substance mixture into a particle size requiredfor inhalation, the particle size being less than 10 μm;

c) optionally preparing a homogenous mixture of the desired substanceswhen each substance has been introduced from stage b) as separatefine-grained particles;

d) conditioning said substance or substance mixture by treatment with awater containing vapour phase in a controlled fashion; and

e) drying.

The conditioning step is carried out by treatment with a watercontaining vapour phase. Said water containing vapour phase is a watervapour phase with or without any organic solvent vapour present.

The conditioning step is carried out at a temperature/relative humiditycombination, which suppresses the glass temperature of substancesinvolved below the process temperature. The glass temperature (T_(g)) isthe temperature at which the mobility of an amorphous material undergoeschanges from an immobile glassy state to mobile rubbery state (phasetransition).

The conditioning is generally carried out at a temperature between 0°and 100° C., preferably between 10 and 50° C. Of practical reasons theconditioning is often performed at ambient temperature. The relativehumidity (RH) at which the conditioning is carried out is chosen so thatthe phase transition occurs, mainly above 35% RH, preferably above 50%RH, and most preferably above 75% RH. The time used is considerablyinfluenced by the batch size, relative humidity and packing etc and maybe from minutes to days.

The final formulation may also include different additives, e.g. asubstance which enhances the absorption of a pharmacologically activedrug in the lung. The enhancers used can be any of a number of compoundswhich act to enhance absorption through the layer of epithelial celllining the alveoli of the lung and into the adjacent pulmonaryvasculature. Among the substances with known absorption-enhancingproperties are surfactants, such as alkali salts of fatty acids, sodiumtauro-dihydrofusidate, lecithins, sodium glycocholate, sodiumtaurocholate, octylglucopyranoside and the like.

Other additives in the formulation may be carriers, diluents,antioxidants, buffer salts and the like, all of which will be treatedaccording to the process of the present invention.

The accuracy and reproducibility of doses are often not sufficient whenusing very small doses in an inhalation device. Therefore very potentdrugs may be diluted with a carrier in order to get an amount of powdersufficient to obtain a reliable and reproducible dose. Such a carriermay be carbohydrates like lactose, glucose, fructose, galactose,trehalose, sucrose, maltose, raffinose, maltitol, melezitose, starch,xylitol, mannitol, myoinositol, and the like and its hydrates,preferably lactose and mannitol, and amino acids such as alanine,betaine and the like.

Coarser particles having a size above 10 μm may also be conditionedusing the process according to the present invention.

The present invention may be applied to for example the followingpharmacologically active substances:

Formoterol (e.g. as fumarate) and salmeterol (e.g. as xinafoate) arehighly selective long-acting β₂ -adrenergic agonists havingbronchospasmolytic effect and are effective in the treatment ofreversible obstructive lung ailments of various genesis, particularlyasthmatic conditions. Salbutamol (e.g. as sulphate), bambuterol (e.g. ashydrochloride), terbutaline (e.g. as sulphate), fenoterol (e.g. ashydrobromide), clenbuterol (e.g. as hydrochloride), procaterol (e.g. ashydrochloride), bitolterol (e.g. as mesylate) and broxaterol are highlyselective β₂ -adrenergic agonists and ipratropium bromide is ananticholinergic bronchodilator. Examples of antiinflammatoryglucocorticoids are budesonide,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione,fluticasone (e.g. as propionate ester), beclomethasone (e.g. asdipropionate ester), tipredane, momethasone and the like. Several of thecompounds could be in the form of pharmacologically acceptable esters,salts, solvates, such as hydrates, or solvates of such esters or salts,if any.

The preferred substances to which the invention is to be applied areterbutaline sulphate, salbutamol sulphate, fenoterol hydrobromide,ipratropium bromide, bambuterol hydrochloride, formoterol fumarate andsalmeterol xinafoate, and their solvates, especially their hydrates.

The most preferred substance mixture to which the invention is to beapplied is formoterol (as formoterol fumarate dihydrate)/lactose(monohydrate), although the same principle may be applied tocombinations such as salbutamol (as salbutamol sulphate)/lactose,terbutaline (as terbutaline sulphate)/lactose, ipratropiumbromide/lactose, budesonide/lactose,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/mannitol,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/myoinositoland(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/lactose.When one of the components is rather insoluble in water, it is possibleto use an organic solvent as a conditioning agent for one compound andwater vapour as a conditioning agent for the other one in theconditioning step. In that case the conditioning may be carried out in atwo step procedure wherein the first step is conditioning with anorganic solvent followed by conditioning by water vapour in a secondstep; or vice versa.

The rearrangement or conditioning of the substance or substance mixture,amorphous or partly amorphous, involve treatment of the substance(s)with a water containing vapour phase in a controlled fashion. Thisconditioning step is to be performed in a defined environment withcontrolled and adjustable humidity or a column using inert gas and/ororganic solvent vapour containing the required amount of water vapour.The packing of the substance or substance mixture affects the timeneeded as well as the result of the conditioning. The tendency of cakingis affecting the number and size of particles. In case of a substancemixture, it is usually an advantage to mix the substances before themicronizing step in order to ensure a homogenous mixture when usingsmall ratios between the drug substance and the additive.

With the present invention it is possible to condition two or moresubstances in the same process while the particle distribution ismaintained and this is from a technical standpoint a great advantage.

The ratio between the substances in a substance mixture is between 1:1and 1:1000, preferably between 1:1 and 1:500, and most preferred between1:1 and 1:200 in the case where one substance is a pharmacologicallyactive substance and the other one is an additive.

The particle size of the fine-grained substances should be identicalbefore and after the conditioning step as measured by differentinstruments like Malvern Master Sizer, Coulter Counter or a microscope.

It is also of utmost importance that the particles obtained arewell-defined in size and distribution as well as have small batch tobatch variations in order to obtain agglomerates that will completelydisintegrate into its primary particles in the inhaler used.

It is an object of the present invention to provide a reliable process,where the drug formulation of a single drug substance or a combinationof a drug substance/additive, preferably formoterol fumaratedihydrate/lactose can be conveniently and reproducibly prepared.

For some material such as formoterol/lactose, where the T_(g) (the glasstransition temperature, the temperature at which the mobility of anamorphous substance undergoes changes from an immobile glassy state tomobile rubbery state) or water sensitivity is markedly different for thedrug substance and the additive, the process can be performed in twosubsequent steps, i.e. conditioning of one substance at onetemperature/RH combination followed by conditioning at a highertemperature/RH for a second substance.

The mixing step is preferably performed before the micronization step inorder to ensure the content uniformity or in a single step using avibratory ball mill as reported by I. Krycer and J. A. Hersey in Int. J.Pharm. 6, 119-129 (1980). It is also possible to mix the substancesafter micronization or after each substance has been conditioned.

In some instances it has been possible to use infrared spectroscopy inorder to study the conversion of an amorphous form or a partlycrystalline form into a stable crystalline form. Other methods availableinclude BET gas adsorption, X-ray powder diffraction, isothermalmicrocalorimetry and differential scanning calorimetry (DSC). We havefound that BET gas adsorption and isothermal microcalorimetry being thebest methods for distinguishing the different forms of the testedcompounds.

When a substance or substance mixture is agglomerated and used as such,a drop of about 70-80% of the respirable particles is found when exposedto high humidity. It has astonishly been found that a drop of only about25-30% occurs when a substance or substance mixture has been conditioned(at 50% RH for formoterol fumarate dihydrate/lactose mixture) beforeagglomeration and exposed to high humidity. After further conditioningat 75% RH a drop of only 5-10% of the respirable particles will occur.There is no difference in particle distribution as measured by a Malverinstrument before and after conditioning at 75% RH. If the conditioningis performed with the agglomerated product the particle distribution isconsiderable worse and the formulation useless in an inhalation device.

Experimental Procedure

The invention relates to the following procedure:

1. Mixing the drug substance with the additive in a defined ratio.

2. Micronizing the mixture.

3. Conditioning at a temperature/relative humidity combination, whichsuppresses the glass temperature of substances involved below theprocess temperature. The glass temperature (T_(g)) is the temperature atwhich the mobility of an amorphous material undergoes changes from animmobile glassy state to mobile rubbery state.

4. Drying with dry nitrogen or air, or in vacuum.

EXAMPLES

The invention is further illustrated but not limited by the followingexamples performed according to the described experimental procedure.Several batches of each substance or substance mixture have beenmeasured. The data represents a comparison of the heat (J/g) given offby non-conditioned and conditioned substances when subjected to a watercontaining vapour phase. The experiments are performed by using aThermal Activity Monitor 2277 (Thermometrics AB, Sweden).

    ______________________________________                                        Example 1                                                                     Salbutamol sulphate (25%)/lactose (75%)                                       Conditioned at relative humidity (RH)                                                                    50-60% RH                                          Non-conditioned substance (J/g)                                                                          5-8                                                Conditioned substance (J/g)                                                                              <0.5                                               Example 2                                                                     Ipratropium bromide (6%)/lactose (94%)                                        Conditioned at relative humidity (RH)                                                                    50-60% RH                                          Non-conditioned substance (J/g)                                                                          6-8                                                Conditioned substance (J/g)                                                                              <0.5                                               Example 3                                                                     Formoterol fumarate dihydrate                                                 Conditioned at relative humidity (RH)                                                                    75% RH                                             Non-conditioned substance (J/g)                                                                          6                                                  Conditioned substance (J/g)                                                                              <0.5                                               Example 4                                                                     Lactose (see FIG. 1)                                                          Conditioned at relative humidity (RH)                                                                    50% RH                                             Non-conditioned substance (J/g)                                                                          10-14                                              Conditioned substance (J/g)                                                                              <0.5                                               Example 5                                                                     Melezitose                                                                    Conditioned at relative humidity (RH)                                                                    50% RH                                             Non-conditioned substance (J/g)                                                                          12                                                 Conditioned substance (J/g)                                                                              <0.5                                               Example 6                                                                     Formoterol fumarate dihydrate (2%)/lactose (98%)                              Conditioned at relative humidity (RH)                                                                    50% RH                                             Non-conditioned substance (J/g)                                                                          10-14                                              Conditioned substance (J/g)                                                                              <0.5                                               ______________________________________                                    

During a recrystallization a large amount of heat is evolved, and bymonitoring the colorimetric signal the sample is checked for anyamorphous content. FIG. 1 shows micronised lactose before (I) and after(II) conditioning. Thus, a complete crystallinity has been obtainedduring the conditioning according to the invention.

We claim:
 1. A process for providing a stable crystallinic form to afine-grained substance or a substance mixture, which can be produced,stored and used while maintaining the aerodynamic properties requiredfor inhalation of such a substance or a substance mixture, whichcomprises the steps ofa) in the case of a substance mixture, eitherpreparing a homogenous mixture of the substances or leaving thecomponents of the mixture separate; b) micronizing, direct precipitatingor diminishing by any conventional method the substance(s), or substancemixture into a particle size required for inhalation, the particle sizebeing less than 10 μm; c) preparing a homogenous mixture of the desiredsubstances in the case wherein each substance has been introducedseparately from stage b) in the form of fine-grained particles; d)conditioning said substance or substance mixture by treatment with awater-containing vapour phase in a controlled fashion; and e) drying thesubstance or substance mixture and wherein said substance or at leastone of the substances of said substance mixture is selected from thegroup consisting of formoterol; salmeterol; salbutamol; bambuterol;terbutaline; fenoterol; clenbuterol; procaterol; bitolterol; broxaterol;ipratropium bromide; budesonide;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;fluticasone; beclomethasone; tipredane; momethasone; pharmacologicallyacceptable esters, salts and solvates thereof; and solvates of suchesters or salts.
 2. A process according to claim 1 wherein theconditioning, in the case of a substance mixture, may be performed in aone-step procedure or a multistep procedure using different relativehumidity/temperature combinations.
 3. A process according to claim 1wherein the substance or substance mixture is a drug formulation of asingle drug substance or a drug substance/additive combination.
 4. Aprocess according to claim 1 wherein said substance or at least one ofthe substances of said substance mixture is selected from the groupconsisting of formoterol fumarate, salmeterol xinafoate, salbutamolsulphate, bambuterol hydrochloride, terbutaline sulphate, fenoterolhydrobromide, clenbuterol hydrochloride, procaterol hydrochloride,bitolterol mesylate, fluticasone propionate, beclomethasone dipropionateand solvates thereof.
 5. A process according to claim 3 applied to adrug substance/additive combination wherein the additive is a carrierselected from the group consisting of lactose, glucose, fructose,galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose,starch, xylitol, mannitol, myoinositol, hydrates thereof, and aminoacids such as alanine and betaine.
 6. A process according to claim 3applied to a drug substance/additive combination wherein the additive isan enhancer selected from a surfactant, such as an alkali salt of afatty acid, sodium taurodihydrofusidate, a lecithin, sodiumglycocholate, sodium taurocholate and octylglucopyranoside or anantioxidant or a buffer salt.
 7. A process according to claim 1 appliedto a substance mixture, wherein said substance mixture is selected fromthe group consisting of formoterol/lactose, salbutamol/lactose,terbutaline/lactose, ipratropium bromide/lactose, budesonide/lactose,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/mannitol,(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/myoinositoland(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione/lactose.8. A process according to claim 1 applied to a substance mixture,wherein said substance mixture is selected from formoterol fumaratedihydrate/lactose, salbutamol sulphate/lactose and terbutalinesulphate/lactose.
 9. A process according to claim 1 wherein step d) iscarried out at a temperature between 0° and 100° C. and at a relativehumidity whereat the phase transition occurs.
 10. A process according toclaim 1 applied to a substance mixture, wherein the ratio between thesubstances in the mixture is between 1:1 and 1:1000.
 11. A processaccording to claim 5, wherein the carrier is lactose or mannitol.
 12. Aprocess according to claim 9, wherein step d) is carried out at atemperature between 10° and 50° C.
 13. A process according to claim 9 or12 wherein the relative humidity in step d) is above 35%.
 14. A processaccording to claim 12 wherein the relative humidity is above 50%.
 15. Aprocess according to claim 14 wherein the relative humidity is above75%.
 16. A process according to claim 10 wherein the ratio between thesubstances is between 1:1 and 1:200 and wherein one substance is apharmacologically active substance and the other is an additive.
 17. Aprocess according to claim 1 wherein step d) is carried out at atemperature/relative humidity combination which suppresses the glasstemperature of the substance involved below the process temperature. 18.A substance or substance mixture produced by the process according toclaim 1 or
 4. 19. A substance mixture produced by the process accordingto claim 5 or
 6. 20. A substance mixture produced by the processaccording to claim 7 or
 8. 21. A substance or substance mixture producedby the process according to any one of claims 9, 10, 12 and 14-17.
 22. Asubstance or substance mixture produced by the process according toclaim 13.